Master detox molecule boosts immune defenses

Scientists have discovered a so far unknown molecular mechanism by which the human immune system activates its immune cells: T cells, a particular type of white blood cells, effectively ward off pathogens if a gene known as Gclc is expressed within them. The Gclc gene encodes a protein instrumental for the production of a substance called glutathione - a molecule that was previously known only to eliminate harmful waste products of metabolism such as reactive oxygen species and free radicals.

Researchers has discovered that glutathione also stimulates T cells' energy metabolism. This way, when in contact with pathogens, T-cells can grow, divide and fight off intruders such as viruses. Glutathione is thus an important molecular switch for the immune system. This discovery offers starting points and perspectives to develop new therapeutic strategies for targeting cancer and autoimmune diseases.

The scientists published their findings today in the journal, Immunity.

"Our body has to keep our immune system in a carefully balanced equilibrium", says the author. "If the body's innate defences are overactive, then they turn against the body. This is what happens in autoimmune diseases like multiple sclerosis or arthritis, for example. However if the defences are too weak, then infections cannot be handled or body cells can proliferate uncontrolled and grow to form tumors, which can become life threatening."

Immune cells such as T cells therefore normally reside in a state of alert hibernation, with their energy consumption reduced to a minimum. If pathogens or parts thereof dock onto their outer envelope, then the T cells wake up and boost their metabolism. This necessarily creates greater amounts of metabolic waste products, such as reactive oxygen species (ROS) and free radicals, which can be toxic for the cells.

When the concentration of these oxidants increases, the T cells have to produce more antioxidants so as not to be poisoned. No previous research group had studied the mechanism of action of antioxidants in T cells to great detail before. In exploring this phenomenon, the team discovered that the antioxidant glutathione produced by T cells serves not only as a garbage collector to dispose of ROS and free radicals, it is also a key switch for energy metabolism that controls the immune response, and is thus of high relevance to various diseases.

For their investigations, the scientists employed genetically modified mice in whose T cells the Gclc gene was removed and therefore these cells could not produce glutathione. "In these mice, we discovered that the control of viruses is impaired - mice that lack the Gclc gene have an immunodeficiency. But by the same token, this also meant the mice could not develop any autoimmune disease such as multiple sclerosis."

Further tests demonstrated the reason for this: "The mice cannot produce any glutathione in their T-cells," author continues, "and so a number of other signalling events that directly boost metabolism and increase energy consumption are lacking." As a result, without glutathione, T-cells do not become fully functional; they remain in their state of hibernation and no self-destructive autoimmune response occurs.

A number of different autoimmune diseases, for example, are related to malfunctions in various subgroups of T cells. "If we understand the differences in the molecular mechanisms by which they stimulate their metabolism during defensive or autoimmune responses, then we can discover clues as to possible attack points for therapeutic agents regulating the immune response." The distinguished researcher sees a similar situation in cancer: "In this context too, it is important to know why the immune cells that are actually supposed to fight cancer cells drop to a low metabolic state and in some cases even actively suppress an immune response against the tumor. Counteractive metabolism-stimulating measures could make the immune cells work more efficiently and fight off cancer more effectively."